Biopunk: Dire Wolves versus Humanized Flies

 

TL;DR. This conversation needs two biological terms—“alleles” and “transgenics”—and one bit of business jargon—“marcom”.

Sometimes weird things happen. Here I am, minding my own business, trying to write a blog about something I call “transgenic anthropomorphic genomes” (a follow up to this post) and marcom at some tech startup drops a video about how they “de extincted” the dire wolf.

Honestly, at first, I ignored it because it was so obviously false. When big science breakthroughs are coming, everyone in the field knows about it before some random marketing video. Remember when Thermo dropped the orbitrap? Everyone in mass spectrometry was talking about it. A fifth form of mass analyzer. This is going to change everything—and it did.

I’d been wanting to write some more about the biopunk elements in my game, Rubble and Ruin. I had things I wanted to talk about. I was researching specifics and gathering figures—all the things academic gamers do before making public statements. And then Colossal Biosciences announced that they had “de extincted” dire wolves. Anyone reading this more than a few months into the future will have forgotten about the announcement—it is just a bunch of misleading corporate marketing designed to attract attention. So, I’ll leave a link here to the story.

According to Science News – sited above – this Texas-based company isn’t really trying to recreate real dire wolves, instead Beth Shapiro, chief science officer at Colossal Biosciences said they wanted to create grey wolves as big as the old dire wolves. And if this is truly what the company is trying to do, then this is definitely #biopunk!

What they did. I’m not going to try and attribute who did what task. The company is the last player in an absolutely long list of scientific teams solving different problems. But, in short, they created a transgenic modern wolf that will have the size (allegedly) of a dire wolf and the color of a fictional wolf from Game of Thrones. And they did this by identifying which genes need to be altered, and then recreating allele sequences from information recovered in ancient DNA.

Public Response. I am a Hank Green fanboy, and he immediately posted this video and then not too much later he posted this follow-up which gives us an hour of Hank Green talking about this. And there are endless other groups dropping videos, but I’ll leave finding them as an exercise for interested readers. (Except I will call out Skepchick just ‘cause.)

Key point. The key point is that these animals are not really dire wolves, instead this company analyzed a source genome (dire wolf), identified how to change several genes in another genome (grey wolf), and then made a transgenic grey wolf which had the phenotypic trait of size that was expressed from the first genome in the second. I’m skipping the “changing the color of the coat” bit, because that appears to be bog-standard transgenics.

There are several things that are—in my humble opinion—missing from this conversation, and I think the easiest way to get there is to talk about humanized flies!

Humanized flies. In my day job I do bioinformatics for children’s health research. This finds me sitting on two different triage meetings. Now I am not a clinician, and I certainly don’t play one on at these meetings, but from time-to-time I have modest contributions to make to help shorten the diagnostic odyssey of some children born in our province, so I’m invited to these meetings. When a child presents at clinic with evidence of an inborn error of metabolism—a metabolic birth defect—it can often take years for the child and family to get a diagnosis and any indication of prognosis. We are running an experimental system to try and shorten this time.

The first meeting I sit on is for patients that have been referred for whole exome sequencing. This is where we sequence all of the parts of the patient’s genome that are expressed as proteins. And, it is a great thing for patients and their families and is rapidly becoming a common testing practice in developed countries. The idea is to sequence every gene in the child at once, rather than the old approach which would test a handful of suspected genes, then if none of them lit up, try another set.

With the whole exome approach, about one in three patients gets a diagnosis within a few months. About one in three gets an answer that nothing was found (which is helpful in accelerating the search for alternative diagnoses), but what is important here is that last third (approximately). They come back with variants of unknown significance—aka Vous’—these are previously unknown genetic variations which may or may not be linked to the patient’s condition.

 Which brings us to the second triage meeting I sit on. Once a month, about a half dozen clinician-scientists and another half dozen research scientists join together to talk about those patients without a clear diagnosis. Is there anything we can do as research scientists to clarify if VOUS discovered during whole exome sequencing is causing the patients’ condition? (As an aside, all of this is through the appropriate IRBs and none of the researchers access any patient identifiable data.)

At this point let’s meet our first English word that is not showing up in the dire wolf conversation, “allele”. If a gene is a locus (or a place) on a DNA strand, then an allele is the specific form of that gene in a given organism. I might have one allele of a gene while you have another. Of course, where all diploid so we each have two alleles of each gene—but often they have the same sequence. Sometimes whole exome sequencing finds an allele of a protein that could—for various reasons—be the source of the patient’s problem. From time-to-time our group decides that the best course of action is to humanize a fly and make a transgenic with this allele.

I have a colleague here in Manitoba that runs a lab that does this. What he does is he knocks out (or removes) the fly’s original copy of the gene and adds it to a human version. The fly now has the candidate defective human allele. If the fly develops normally, this is evidence that the vous is not causing the disease in the patient. But if the patient has, for example, neurological symptoms and the fly develops neurological abnormalities, then this is evidence that the new allele impacts neurological development.

Did you notice how I slipped in the word ‘transgenic’? A transgenic organism is simply one where the DNA from another organism, usually another species, has been artificially added to it. Our flies are transgenic. And when you add the entire human gene, we call it a humanized transgenic. Humanity has been making transgenics for over half a century. It is not inherently interesting or unique—I mean it is cool, but most research hospitals will have a transgenic core facility staffed with scientists who can make them to order.

It is my understanding that to make a humanized gene, you typically start with growing human cells and extract the gene, then modify it to the desired sequence based on the patient-derived information and then insert it into a fly. (Don’t hold me to this, I’m writing this over the weekend at home and can’t check with the people who actually do this sort of work.) The interesting part is that the information for the desired allele comes from the patient—but no biological material does.

Back to dire wolves. For the wolves, something like 15* alleles unique to dire wolves were identified. These alleles were on homologous genes (which means the genes were identical due to common descent) between both species. And likely common to dogs—which would explain how the company would be able to recognize them as being associated with the traits of interest, hair color, size, and skull shape.

You can’t culture dire wolf cells, because none are alive to start with. So, they cultured modern wolf cells. You can’t “dire-wolf-ize” the cells—same reason. But you can make a transgenic with an allele sequence matching that of the extinct dire wolf.

This is interesting in a biopunk sort of way, but not revolutionary science.

Marcom. Which brings us to our last word, marcom. Marcom is business slang for the Marketing and Communications group. If I head out of my little office at my day job, swipe one of the three access cards I wear around my neck, head down the hall past the various research facilities on my floor, and out into the administrative area—there is a door labeled  Marcom. It is for our parent organization’s Marketing and Communications group. At my last job I spent a lot of time interacting with (or better said, reacting to) the Marcom group for a large multi-national corporation we partnered with.

Marcom controls the message and brand of a corporation. Marcom answers to Legal, not to peer review. They can say anything they want, bound only by the law, not the truth. They want to say that dire wolves have been recreated. It’s legal for them to say that. It’s not true, but that’s not the test. (Side note, my current job’s marcom is full of great people who hold the truth in high regard—but they also don’t work for a tech start-up trying to raise venture capital.)

Conclusions. Humanized flies are not people, and transgenic wolves are not dire wolves. Both are useful and interesting, and both show how humanity is starting to take control over the living world. Not just by changing the environment but also by changing the living elements of the ecosystem, by creating new forms of life custom built to achieve specific goals. In my next post I will write about what I feel is one of the greatest unasked questions heading towards humanity, but for now let’s add some words to this discussion—alleles, transgenics, and marcom

 As always, thanks for reading and comments are welcome below.

 

* They say that five alleles were related to coat color, which would not have come from the dire wolf sequences, so I'm saying 20-5 or 15.